Activation of the renin-angiotensin system (RAS) is associated with increased cardiovascular death. A critical component of this system is angiotensin converting enzyme (ACE), which cleaves angiotensin I to angiotensin II (Angll). In humans, increased Angll levels are associated with an increased ventricular arrhythmic risk. Nevertheless, the reasons for the increased risk are unclear. One critical effect of RAS activation is Angll-induced oxidative stress mediated, in part, by increased NADPH oxidase activity. We hypothesized that oxidative stress caused by Angll induced cardiac arrhythmias. To investigate this, we developed a cardiac-restricted ACE overexpression mouse (ACE 8/8) that showed an increased risk of sudden death in the absence of heart failure or structural heart disease. Intracardiac recordings demonstrate poor conduction and various forms of AV nodal block. Ventricular pacing readily induced ventricular tachycardia. This phenotype is associated with reductions in cardiac sodium channels. We have developed preliminary data that Angll-mediated oxidative stress activates the transcription factor NFkB resulting in downregulation of the cardiac sodium channel. In this proposal, we hypothesize that increased Angll leads to oxidative stress which in-turn alters sodium channel transcription through NFkB activation. An altered ion channel level contributes to the ACE 8/8 mouse arrhythmic phenotype. This proposal is a plan to dissect the steps in this putative cascade and to identify which are proximate causes, which are upstream events, and which are associated but not causative steps. In each aim, we will establish to what extent measures of the sodium channel, NFkB activation, oxidative stress, and arrhythmic risk are altered by the disruptions in the proposed signaling cascade. Specific Objectives. Specific aim 1: To establish to what extent Angll-mediated signaling is responsible for the sodium channel regulation in our ACE overexpression model. Specific aim 2: To establish to what extent NADPH oxidase activation is responsible for the sodium channel regulation in our ACE overexpression model. Specific aim 3: To establish to what extent increased NFkB activation is responsible for the sodium channel regulation in our ACE overexpression model. This application presents a novel hypothesis about why RAS activation causes arrhythmias, contributing to atrial fibrillation (AF) and heart failure (HF)-associated sudden death.